The growing use of phenelzine in the treatment of depressive disorders and the affective neuroses warrants additional study to investigate both its efficacy and pharmacokinetics during long-term maintenance treatment. There have been few studies evaluating the effectiveness of antidepressant drug maintenance therapy and most have been short-term. To our knowledge there have been no reports of long-term controlled clinical trials of MAOIs despite their growing use and increasingly broad indications in clinical practice. Dosage guidelines for maintenance treatment with phenelzine and other MAOIs are unclear. Pharmacokinetics and drug metabolism with chronic use need to be investigated. The specific aims of the proposed long-term treatment study of outpatients with Major Depressive Disorder are to assess the therapeutic efficacy of phenelzine in preventing recurrent depressive episodes over a 2-year period after recovery from an index episode; to establish the effective maintenance dosage of phenelzine (based on mg/kg/day); and to determine if there is a critical threshold dosage. Phenelzine pharmacokinetics using heavy isotope-labeled drug will be studied during the initial, continuation and maintenance treatment phases to determine if clearance and elimination of the drug is altered. Evidence for nonlinear kinetics of phenelzine and its gradual accumulation in plasma over the initial months of treatment will be examined and related to platelet MAO inhibition. The investigators have carried out prior studies which strongly suggest that phenelzine is in part metabolized by the enzyme, monoamine oxidase, such that its half-life is dose-dependent and significantly prolonged during continuous treatment. Patients meeting RDC criteria for Major Depressive Disorder with at least one previous life-time episode will be eligible for admission to his protocol. Patients will be treated openly with phenelzine in standard dosages and remain in continuation therapy until they have been symptom free for 20 consecutive weeks. Patients then will be randomized to 3 groups; phenelzine 60 mg/day, phenelzine 45 mg/day and placebo. Patients will be seen at least monthly during the 2-year maintenance phase and monitored for recurrence of symptoms. Patients will be discontinued when recurrence is documented, and treated according to standard practice. Statistical analysis will include appropriate multivariate techniques including survival and end point co-variance analysis.